Results of the Women's Health Initiative Memory Study which indicated an increased risk of Alzheimer's disease (AD) in women treated with hormone therapy (HT) led to a reevaluation of the benefits versus harm of hormone interventions. As part of this reevaluation, disparities between the beneficial outcomes of estrogen (E2, ET) and progesterone (P4) found in basic science analyses and the adverse outcomes of clinical trials were clear as were the disparities between the generally positive outcomes of ET and HT in observational studies versus the deleterious outcomes of clinical trials. The Progesterone in Brain Aging and Alzheimer's Disease Program Project is designed to address key elements hypothesized to underlie these disparities as well as addressing the paucity of knowledge regarding the neurobiology of progesterone (P4) action in brain regions required for cognition and vulnerable to age associated degenerative disease such as Alzheimer's. The over arching hypothesis of our program is that the ovarian steroid hormone progesterone promotes the brain's molecular, synaptic, cellular, and behavioral plasticity and reduces its vulnerability to the development of Alzheimer's disease (AD). Specifically, we hypothesize that progesterone has direct effects via activation of progesterone receptors in hippocampus and indirect effects via interaction with estrogen pathways. We further hypothesize that the reproductive endocrine status, duration of ovariprivation and presence of AD related pathology regulates the plasticity response to ovarian steroids. We have designed the Program Project to investigate P4 action at 7 levels of function from molecular to behavioral to exacerbation of AD-like pathology in vivo. Embedded in each proposal is an assessment of: (1) P4 receptor expression; (2) direct effect of P4 on neural plasticity; (3) clinically relevant progestins for their comparability to P4; (3) change in response to E2 and P4 with reproductive endocrine status, age or duration of ovariprivation and (4) E2 and P4 regulation of neural plasticity or inflammatory responses in a triple transgenic mouse model of Alzheimer's disease. Our long-term goals are three fold: (1) To establish a foundation of P4 neurobiology in brain regions required for cognitive function and vulnerable to Alzheimer's disease. (2) To develop rodent models of human perimenopause and menopause for both our investigations and those within the field of women's health. (3) To provide insights into the basis of disparities between basic science outcomes and clinical trial outcomes as well as the disparities between observational studies and clinical trials of HT and AD.